Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL

Qiang Wen, Benjamin Goldenson, Serena J. Silver, Monica Schenone, Vlado Dancik, Zan Huang, Ling Zhi Wang, Timothy A. Lewis, W. Frank An, Xiaoyu Li, Mark Anthony Bray, Clarisse Thiollier, Lauren Diebold, Laure Gilles, Martha S. Vokes, Christopher B. Moore, Meghan Bliss-Moreau, Lynn Verplank, Nicola J. Tolliday, Rama MishraSasidhar Vemula, Jianjian Shi, Lei Wei, Reuben Kapur, Cécile K. Lopez, Bastien Gerby, Paola Ballerini, Francoise Pflumio, D. Gary Gilliland, Liat Goldberg, Yehudit Birger, Shai Izraeli, Alan S. Gamis, Franklin O. Smith, William G. Woods, Jeffrey Taub, Christina A. Scherer, James E. Bradner, Boon Cher Goh, Thomas Mercher, Anne E. Carpenter, Robert J. Gould, Paul A. Clemons, Steven A. Carr, David E. Root, Stuart L. Schreiber, Andrew M. Stern*, John D. Crispino

*Corresponding author for this work

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.

Original languageEnglish (US)
Pages (from-to)575-589
Number of pages15
JournalCell
Volume150
Issue number3
DOIs
StatePublished - Aug 3 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Wen, Q., Goldenson, B., Silver, S. J., Schenone, M., Dancik, V., Huang, Z., Wang, L. Z., Lewis, T. A., An, W. F., Li, X., Bray, M. A., Thiollier, C., Diebold, L., Gilles, L., Vokes, M. S., Moore, C. B., Bliss-Moreau, M., Verplank, L., Tolliday, N. J., ... Crispino, J. D. (2012). Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL. Cell, 150(3), 575-589. https://doi.org/10.1016/j.cell.2012.06.032